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Vaccines, Blood & Biologics

DPQ Review Memo - IXIARO


Date:March 30, 2009
To:Dr. Lewis Markoff, HFM-451
From:William McCormick, Ph.D., HFM-407
Through:Dr. Norman W. Baylor, Office Director OVRR/CBER
Subject: Review of STN 125280/0/0: Intercell Biomedical Ltd, – Japanese Encephalitis Vaccine, Inactivated, Adsorbed; Review of -(b)(4)- ID assay for Lot Release of Drug Product submitted with Response to the CR Letter Question 2 as a part of Amendment 11.

From CBER letter dated September 26, 2008, the following deficiency was described:


Question 2.

“Your proposed test procedures and acceptance criteria for release testing of drug substance are inadequate because you have not indicated an identity test. An identity test on the final product is required for lot release under 21CFR610.14. Identity may be established either through the physical or chemical characteristics of the product, inspection by macroscopic or microscopic methods, or in vivo or in vitro immunologic tests. We acknowledge that you have developed an -(b)(4)- , as you noted in your previous response. If you wish to submit the -(b)(4)- in support of product identity, you will need to submit data regarding the -(b)(4)- for FDA review. Also, in your communication of August 11, 2008, you suggest that product identity was established by -----------(b)(4)----------------------, by in-process ----(b)(4)----, and by the ---------(b)(4)---------- assay. Please note that neither ------------(b)(4)--------------- nor the in-process ----(b)(4)----- is acceptable for identity, because they are not performed on the final product. If you wish to use the --(b)(4)-- assay as a surrogate for identity, you will need to submit the appropriate documentation supporting the use of this assay as a measure of product identity.”


[In response to CBER’s comments on the original submission conveyed to Intercell as Question 2 on September 26, 2008 as part of the complete response letter, the applicant submitted Amendment 11 to provide documentation to support the use of -(b)(4)- as an identity test for release testing of drug product.]

Intercell has chosen to introduce a highly specific JEV antigen -(b)(4)- performed on Drug Substance and on final Drug Product after -----------------(b)(4)---------------- for the purpose of Lot Release.

The following documents were submitted to support the use of -(b)(4)- as an identity test.

1. SOP GTP-BP-001, version 4, -(b)(4)- for the determination of Inactivated viral antigen in samples of the Japanese encephalitis virus vaccine manufacturing process

2. Validation Report TSS3914B: Validation of an -(b)(4)- for the quantitation of inactivated Japanese encephalitis virus from the JEV vaccine manufacturing process

3. Technical Report. Specificity of antibodies used in immunological assays for quantitation, characterization and identity testing of IC51 with regard to potential flavivirus cross-reactivity

4. Development Report. DR-AFD-0182-01. Qualification and Reproducibility of a desorption procedure for JEV-DP.


The method is a -------------------------------------------(b)(4)


---- -------------------------------------------------------------------------------. Specificity of the antibodies to JEV has been demonstrated by two studies that each demonstrated no cross-reactivity with ---------(b)(4)--------- virus and very minimal cross-reactivity with ----(b)(4)---- virus seen at a -(b)(4)- -fold lower signal. The method is suitable as an identity test.

It has been proposed that this same assay technology be used for determining potency of the antigen at various stages in the production. The following comment in response (response dated October 1, 2008) to the CR letter (dated September 26, 2008) implies that Intercell believes that their data supports the assay for quantitative purposes. “The -(b)(4)- method for determination of JEV antigen content after ----(b)(4)--- has been fully developed and validated. […] The method was subjected to a full validation according to the ICH guidelines. […] The validation exercise confirmed that the -(b)(4)- method is sufficiently accurate, precise, specific and robust for quantitation of JEV antigen content in samples of -(b)(4)- and drug substance.” Our review has not found the assay to be adequately developed to be used in a quantitative application. The

-----(b)(4)------ plotted by ------(b)(4)------- logistic equation does not include upper and lower asymptotes which are important parameters for defining the performance of this model when used quantitatively. ---(b)(4)--- of JEV from --------------(b)(4)-------------- seems to have lot to lot variability and may not be complete. This variability is, however, acceptable to allow the assay to establish identity of the product. These comments are included in this review in order to facilitate further assay refinement and validation prior to the assay becoming acceptable for determining potency.


Submitted documents support the use of -(b)(4)- method to establish identity of JEV for drug product.

DPQ reviewer team concur that -(b)(4)- test described will be appropriate for ID testing of Drug Product at Lot Release.

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